The term avermectin (previously referred to as C-076) is used to describe a series of compounds isolated from the fermentation broth of a avermectin producing strain of Streotomyces avermitilis. The morphological characteristics of the culture are completely described in Great Britain Pat. No. 1,573,955. The avermectin compounds are a series of macrolides, each of which is substituted thereon at the 13-position with a 4-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose group. The avermectin compounds and the instant derivatives thereof have a very high degree of anthelmintic and antiparasitic activity.
The avermectin series of compounds have the following structure: ##STR1## wherein R.sub.1 is iso-propyl or sec-butyl; and
R.sub.2 is methoxy or hydroxy; PA1 R.sub.3 is the 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyloxy group of the structure: ##STR2## and wherein the broken line indicates a single or a double bond; R.sub.4 is hydroxy and is present only when said broken line indicates a single bond. PA1 R.sub.3 is hydrogen, hydroxy, acetoxy, .alpha.-L-oleandrosyloxy, 4'-acetyl-.alpha.-L-oleandrosyloxy, 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyloxy, 4"-acetyl-4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyloxy, or 4"-(phenoxyacetyl)-4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyloxy; and PA1 R.sub.4 is hydrogen, acetyl, benzoyl, pyridinylcarbonyl, pyrrollylcarbonyl, --CO(CH.sub.2).sub.n COOH or --CO(CH.sub.2).sub.n COOM wherein n is 2, 3 or 4 and M is an alkali metal or an ammonium or diloweralkyl ammonium cation; provided that R.sub.4 is pyrrollylcarbonyl only when R.sub.1 is isopropyl or sec-butyl.
There are eight different avermectin compounds and they are given the designations Ala, A1b, A2a, A2b, B1a, B1b, B2a, B2b based upon the structure of the individual compounds.
In the foregoing structural formula, the individual avermectin compounds are as set forth below.
______________________________________ R.sub.4 R.sub.1 R.sub.2 ______________________________________ A1a Double bond sec-butyl --OCH.sub.3 A1b Double bond iso-propyl --OCH.sub.3 A2a --OH sec-butyl --OCH.sub.3 A2b --OH iso-propyl --OCH.sub.3 B1a Double bond sec-butyl --OH B1b Double bond iso-propyl --OH B2a --OH sec-butyl --OH B2b --OH iso-propyl --OH ______________________________________
The methyl group at the 4-postion of the avermectin macrolide ring is referred to as the 4a carbon atom. The substitution at the 4a position is the subject matter of this invention.
Avermectin compounds, with a hydrogen at the 13-position rather than the oxygen atom which is bonded to the disaccharide moiety, as disclosed in U.S. Pat. Nos. 4,171,134 and 4,173,571 by Chabala et al., are closely related to the milbemycin compounds disclosed in U.S. Pat. No. 3,950,360 to Aoki et al. Such compounds have a methyl or ethyl group at the 25-position rather than the instant isopropyl or sec-butyl group. The compounds, as described in the Aoki et al., patent, are produced by an organism of the genus Streptomyces, strain B-41-146. Certain of the milbemycin compounds are subject to the modifications at the 4a-position of this invention and the structures of such compounds are set forth below. The R.sub.1, R.sub.2 and R.sub.3 designations refer to the above formula.
______________________________________ R.sub.3 Milbemycin 13-position R.sub.4 R.sub.1 R.sub.2 ______________________________________ .alpha.1 --H --H methyl --OH .alpha.2 --H --H methyl --OCH.sub.3 .alpha.3 --H --H ethyl --OH .alpha.4 --H --H ethyl --OCH.sub.3 ______________________________________